Ciprofloxacin is used alone or in combination with other antibacterial drugs in the empiric treatment of infections for which the bacterial pathogen has not been identified, including urinary tract infections[5][6] and abdominal infections[7] among others. It is also used for the treatment of infections caused by specific pathogens known to be sensitive.

Ciprofloxacin is the most widely used of the second-generation quinolone antibiotics that came into clinical use in the late 1980s and early 1990s.[8][9] In 2010, over 20 million outpatient prescriptions were written for ciprofloxacin, making it the 35th-most commonly prescribed drug, and the 5th-most commonly prescribed antibacterial, in the US.[10] Ciprofloxacin was first patented in 1983 by Bayer A.G. and subsequently approved by the US Food and Drug Administration (FDA) in 1987. Ciprofloxacin has 12 FDA-approved human uses and other veterinary uses, but it is often used for unapproved uses (off-label).

Overall, the safety of ciprofloxacin and other fluoroquinolones appears to be similar to that of other antibiotics, but serious side effects occur on occasion. Some disagreement in the literature exists regarding whether fluoroquinolones produce serious adverse events at a higher rate than other broad-spectrum antibiotics.[11][12][13][14][15] The U.S. FDA-approved label for ciprofloxacin includes a "black box" warning of increased risk of tendon damage and/or rupture and for exacerbation of muscle weakness in patients with the neurological disorder myasthenia gravis.[16]

Ciprofloxacin only treats bacterial infections; it does not treat viral infections such as the common cold. Although for certain uses including acute sinusitis, lower respiratory tract infections and uncomplicated gonorrhea, ciprofloxacin is not considered a first-line agent.

Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be caused by Gram-negative bacteria, including Pseudomonas aeruginosa. For example, ciprofloxacin in combination with metronidazole is one of several first-line antibiotic regimens recommended by the Infectious Disease Society of America for the treatment of community-acquired abdominal infections in adults.[18] It also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis,[19] certain types of endocarditis,[20] certain skin infections,[21] and prosthetic joint infections.[22]

In other cases, treatment guidelines are more restrictive, recommending in most cases that older, narrower-spectrum drugs be used as first-line therapy for less severe infections to minimize fluoroquinolone-resistance development. For example, the Infectious Disease Society of America recommends the use of ciprofloxacin and other fluoroquinolones in urinary tract infections be reserved to cases of proven or expected resistance to narrower-spectrum drugs such as nitrofurantoin or trimethoprim-sulfamethoxazole.[23] The European Association for Urology recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for “adverse events have to be considered”.[19]

Although approved by regulatory authorities for the treatment of respiratory infections, ciprofloxacin is not recommended for respiratory infections by most treatment guidelines due in part to its modest activity against the common respiratory pathogen Streptococcus pneumoniae.[24][25][26][27] "Respiratory quiniolones" such as levofloxacin, having greater activity against this pathogen, are recommended as first line agents for the treatment of community-acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for [28][29]

Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development.[30][31][32][33]

Available forms

Ciprofloxacin for systemic administration is available as immediate-release tablets, as extended-release tablets, as an oral suspension, and as a solution for intravenous infusion. It is also available for local administration as eye drops and ear drops.

Pregnancy

The U.S. FDA categorizes ciprofloxacin in pregnancy category C.[34] This category includes drugs for which no adequate and well-controlled studies in human pregnancy exist, and for which animal studies have suggested the potential for harm to the fetus, but potential benefits may warrant use of the drug in pregnant women despite potential risks. An expert review of published data on experiences with ciprofloxacin use during pregnancy by the Teratogen Information System concluded therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state no risk exists.[35]

Two small post-marketing epidemiology studies of mostly short-term, first-trimester exposure found that flouroquinolones did not increase risk of major malformations, spontaneous abortions, premature birth, or low birth weight.[36][37] The label notes, however, that these studies are insufficient to reliably evaluate the definitive safety or risk of less common defects by ciprofloxacin in pregnant women and their developing fetuses.

Breastfeeding

The fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.[38][39] The US FDA recommends that because of the risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Children

Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system:

2) Complicated urinary tract infections and pyelonephritis due to Escherichia coli,[41] but never as first-line agents. Current recommendations by the American Academy of Pediatrics note the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug-resistant pathogens or when no safe or effective alternatives are available.[42]

Adverse effects

Overall, the safety of ciprofloxacin and other fluoroquinolones appears to be similar to that of other antibiotics, but serious side effects occur on occasion. Some disagreement has been reported in the literature regarding whether fluoroquinolones produce serious adverse events at a higher rate than other broad-spectrum antibiotics.[11][12][13][14][15]

In pre-approval clinical trials, 49,038 patients received courses of ciprofloxacin.[43] Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1% of orally treated patients. The most frequently reported drug-related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%.

The black box warning on the US FDA-approved ciprofloxacin label warns of an increased risk of tendinitis and tendon rupture, especially in patients who are older than 60 years, patients who also use corticosteroids, and patients with kidney, lung, or heart transplants. Tendon rupture can occur during therapy or even months after discontinuation of the drug.[44] A case control study[45] performed using a UK medical care database found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The relative risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.1%) cases of Achilles tendon rupture were identified. A study performed using an Italian healthcare database reached qualitatively similar conclusions.[46]

The other black box warning is that ciprofloxacin should not be used in patients with myasthenia gravis due to possible exacerbation of muscle weakness which may lead to breathing problems resulting in death or ventilator support. Fluoroquinolones are known to block neuromuscular transmission. [47]

Clostridium difficile-associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad-spectrum antibiotics.[48]

The 2013 FDA label warns of nervous system effects. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold, and may cause other central nervous system side effects. Headache, dizziness, and insomnia have been reported as occurring fairly commonly in postapproval review articles, along with a much lower incidence of serious CNS side effects such as tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses.[11] Like other fluoroquinolones, it is also known to cause peripheral neuropathy that may be irreversible, such as weakness, burning pain, tingling, or numbness.[49]

A wide range of rare but potentially fatal side effects spontaneously reported to the US FDA or the subject of case reports published in medical journals include, but are not limited to, toxic epidermal necrolysis, Stevens-Johnson syndrome, heart arrhythmias (torsades des pointes or QT prolongation), allergic pneumonitis, bone marrow suppression, hepatitis or liver failure,[50] and phototoxicity/photosensitivity. The drug should be discontinued if a rash, jaundice, or other sign of hypersentitivity occur.[51]

Children and the elderly are at a much greater risk of experiencing adverse reactions.[52][53]

Contraindications

Anyone with a history of hypersensitivity to any member of the quinolone class of antimicrobial agents, including ciprofloxacin, or any of the product components is contraindicated.

Ciprofloxacin is also considered to be contraindicated within the pediatric population (except for the indications outlined above), pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders.

Genotoxicity and carcinogenicity studies

Ciprofloxacin is active in six of eight in vitro assays used as rapid screens for the detection of genotoxic effects, but is not active in in vivo assays of genotoxicity.[55] Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.

Interactions

Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.

Ciprofloxacin should not be taken with antacids containing magnesium or aluminum, highly buffered drugs (sevelamer, lanthanum carbonate, sucralfate, didanosine), or with supplements containing calcium, iron, or zinc. It should be taken two hours before or six hours after these products. Magnesium or aluminum antacids turn ciprofloxacin into insoluble salts that are not readily absorbed by the intestinal tract, reducing peak serum concentrations by 90% or more, leading to therapeutic failure. Additionally, it should not be taken with dairy products or calcium-fortified juices alone, as peak serum concentration and the area under the serum concentration-time curve can be reduced up to 40%. However, ciprofloxacin may be taken with dairy products or calcium-fortified juices as part of a meal.[56][57][58]

Ciprofloxacin inhibits the drug-metabolizing enzyme CYP1A2 and thereby can reduce the clearance of drugs metabolized by that enzyme. CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include tizanidine, theophylline, caffeine, methylxanthines, clozapine, olanzapine, and ropinirole. Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contraindicated due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Use of ciprofloxacin is cautioned in patients on theophylline due to its narrow therapeutic index. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as cyclosporine is equivocal or conflicting.[58][59][60]

Altered serum levels of the antiepileptic drugs phenytoin and carbamazepine (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.[59][63][64]

Overdose

Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or gastric lavage, as well as administration of magnesium-, aluminum-, or calcium-containing antacids to reduce drug absorption. Renal function and urinary pH should be monitored. Important support includes adequate hydration and urine acidification if necessary to prevent crystalluria. Hemodialysis or peritoneal dialysis can only remove less than 10% of ciprofloxacin.[57] Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.[65]

Chemical properties

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.[57]

Ciprofloxacin hydrochloride (USP) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C17H18FN3O3HCl•H2O.[57]

Pharmacokinetics

Ciprofloxacin for systemic administration is available as immediate-release tablets, extended-release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion,[68] ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum. Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations. The serum half-life of ciprofloxacin is about 4–6 hours, with 50-70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites. Urinary excretion is virtually complete by 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment.

Ciprofloxacin is weakly bound to serum proteins (20-40%), but is an inhibitor of the drug-metabolizing enzyme cytochrome P450 1A2, which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme.

Ciprofloxacin is about 70% orally available when administered orally, so a slightly higher dose is needed to achieve the same exposure when switching from IV to oral administration. A 750-mg immediate-release oral tablet given every 12 hours produces about the same area under the serum concentration curve (AUC) and peak serum concentration (Cmax) as a 400-mg dose given every 8 hours IV.[51] The extended release oral tablets[69] allow once-daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate-release form and 65% in a slow-release matrix. Maximum serum concentrations are achieved between 1 and 4 hours after administration. Compared to the 250- and 500-mg immediate-release tablets, the 500-mg and 1000-mg XR tablets provide higher Cmax, but the 24‑hour AUCs are equivalent.

Ciprofloxacin immediate-release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt as the free base.

History

Ciprofloxacin 250-mg tablets from the Ukraine

The first members of the quinolone antibacterial class were relatively low-potency drugs such as nalidixic acid, used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine.[70] In 1979, the publication of a patent[71] filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of norfloxacin, and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency.[72] In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class.

The fluoroquinolone program at Bayer focused on examining the effects of very minor changes to the norfloxacin structure.[73][74] In 1983, the company published in vitro potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure differing from that of norfloxacin by the presence of a single carbon atom.[75] This small change led to a two- to 10-fold increase in potency against most strains of Gram-negative bacteria. Importantly, this structural change led to a four-fold improvement in activity against the important Gram-negative pathogen Pseudomonas aeruginosa, making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen.

The oral tablet form of ciprofloxacin was approved in October 1987,[76] just one year after the approval of norfloxacin.[77] In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached a peak of about 2 billion euros in 2001, representing 34% of Bayer’s total pharmaceutical revenues, before Bayer's patent expired in 2004, after which annual sales have averaged around €200 million.[78][79]

Society and culture

Generic equivalents

On 24 October 2001, The Prescription Access Litigation (PAL) filed suit to dissolve an agreement between Bayer and three of its competitors which produced generic versions of drugs (Barr Laboratories, Rugby Laboratories, and Hoechst-Marion-Roussel) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayer's patent had expired, the United States District Court for the Eastern District of New York granted Bayer's and the other defendants' motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law,[80] in effect upholding Bayer's agreement with its competitors.

Bacterial resistance

As a result of its widespread use to treat minor infections readily treatable with older, less broad spectrum antibiotics, many bacteria have developed resistance to this drug in recent years, leaving it significantly less effective than it would have been otherwise.[81][82]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.[86] Nearly half (42%) of those prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality.[86][87] Additionally, they were commonly prescribed for medical conditions that were not even bacterial to begin with, such as viral infections, or those to which no proven benefit existed.

Litigation

A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the US Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they suffered serious adverse effects from taking ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. The class action was defeated and the litigation abandoned by the plaintiffs.[88] A similar action was filed in 2003 in New Jersey by four New Jersey postal workers but was withdrawn for lack of grounds, as workers had been informed of the risks of cipro when they were given the option of taking the drug.[89][90]

^"International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases".

^Zuger A (3 November 1998). "Ciprofloxacin for Acute Exacerbations of Chronic Bronchitis". Journal Watch (General)1998 (1103): 4. Because of its unpredictable activity against the pneumococcus, ciprofloxacin is not usually considered a first-line treatment for respiratory infections...

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